This study will evaluate the hypothesis that stem cell/progenitor cell failure leads to inadequate repair of tissue and contributes to the development of emphysema. The proposal will also evaluate the related therapeutic implications: by replacing stem cells, the susceptibility of old animals to develop emphysema can be mitigated and the repair of the emphysematous lung can be facilitated. Maintenance of lung structure requires adequate, ongoing tissue repair throughout life. Stem/progenitor cell failure could lead to inadequate repair and subsequent net loss of lung tissue, the defining feature of pulmonary emphysema. The similarity between senile lung that develops, to some degree, in all aging animals and emphysema has been noted and supports this concept. Tissue destruction, for example due to cigarette smoke, is likely to be more disruptive in individuals with inadequate repair. This proposal will determine if pluripotent stem cells can populate the lung and contribute to lung repair. Specifically, the ability of cells derived from old and young animals to repopulate lungs will be assessed using green fluorescent protein (GFP) transgenic mice to provide "marked" stem cells. The ability of these donor cells to repopulate various lung cell compartments will be quantified. The donor cells will be fractionated and characterized using defined cell surface markers. Cells derived from recipient lungs will be assessed for function related to repair in vitro. Finally, the ability of cell transplantation decrease the susceptibility of old animals to develop emphysema will be assessed. The ability of stem cell transplantation to facilitate functional and structural repair of the lung in aged and emphysematous animals will be assessed. These studies will establish a role for stem cells in modulating lung repair and provide evidence that use of such cells could play a role in the therapy of destructive lung disorders such as emphysema.